Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells.
Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells.
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应激激酶 p38α 在介导沙利度胺类似物 CPS49 在癌细胞和内皮细胞中的直接细胞毒性作用中的重要性。
DOI：
10.1158/1078-0432.ccr-05-1837
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Dennis,PhillipA
中科院分区：
文献类型：
--
作者：
Warfel,NoelA;Lepper,ErinR;Zhang,Chunyu;Figg,WilliamD;Dennis,PhillipA
目的：沙利度胺作为癌症治疗剂因其潜在的抗血管生成作用而重新引起人们的兴趣。沙利度胺类似物 CPS11 和 CPS49 在临床前血管生成测定和异种移植模型系统中具有活性，但这些观察结果的生化基础尚不清楚。 实验设计：为了解决这个问题，我们使用测量凋亡和非凋亡细胞死亡的测定法评估了这些沙利度胺类似物在癌细胞、内皮细胞和转基因细胞中的毒性。磷酸特异性抗体和天然抗体用于免疫印迹和免疫组织化学实验，以评估体外和体内控制细胞存活的激酶的激活状态。结果：CPS49 以剂量依赖性方式主要诱导肺癌细胞、前列腺癌细胞和内皮细胞的非凋亡细胞死亡，而 CPS11 没有细胞毒性。 CPS49 不会抑制促进生存的激酶，例如 Akt 或细胞外信号调节激酶，而是快速激活癌细胞和内皮细胞中的应激激酶 p38 通路。 CPS49 激活肿瘤异种移植物中的 p38。使用 p38α−/− 细胞或 p38 抑制剂，我们发现 p38α 的存在和激活对于所有检查的细胞类型的细胞毒性都很重要。结论：我们的研究确定了四氟沙利度胺类似物 CPS49 细胞毒性的统一作用机制，并表明 p38 的激活可以作为 CPS49 临床试验中的生物标志物。
Purpose:Thalidomide has gained renewed interest as a cancer therapeutic due to its potential antiangiogenic effects. The thalidomide analogues CPS11 and CPS49 are active in preclinical angiogenesis assays and xenograft model systems, but the biochemical basis for these observations is unclear.Experimental Design:To address this question, we assessed the toxicity of these thalidomide analogues in cancer cells, endothelial cells, and genetically modified cells using assays that measure apoptotic and nonapoptotic cell death. Phosphospecific and native antibodies were used in immunoblotting and immunohistochemical experiments to assess the activation states of kinases that control cellular survivalin vitroandin vivo.Results:CPS49 predominantly induced nonapoptotic cell death in lung cancer cells, prostate cancer cells, and endothelial cells in a dose-dependent manner, whereas CPS11 was not cytotoxic. CPS49 did not inhibit kinases that promote survival, such as Akt or extracellular signal-regulated kinase, but rather rapidly activated the stress kinase p38 pathway in both cancer cells and endothelial cells. CPS49 activated p38 in tumor xenografts. Using p38α−/− cells or an inhibitor of p38, we show that the presence and activation of p38α is important for cytotoxicity in all cell types examined.Conclusions:Our studies identify a unifying mechanism of action for cytotoxicity of the tetraflourinated thalidomide analogue, CPS49, and suggest that activation of p38 could serve as a biomarker in clinical trials with CPS49.